338
J. Org. Chem. 1993,58, 338-342
Stereoselective Total Synthesis of (*)-Invictolide. An Efficient Preparation of a Trisubstituted &Lactone from Aldol Precursors Ronald0 Aloise Pilli' and Maria Marcia Murta Universidade Estadual de Campinas, Zmtituto d e Qulmica C.P. 6154, 13081 -Campinas, SP, Brazil Received May 12, 1992 (Revised Manuscript Receiued October 20, 1992)
The stereoselective total synthesis of (A)-invictolide (l), a component of the queen recognition pheromone of Solenopsisinuicta, is described. The TiCb-mediated addition of silyl ketene thioacetal 8 to (*)-3-(benzyloxy)-2-methylpropionaldehydeafforded exclusively thioester 10, in 65% yield, which was straightforwardly converted to diol 5 (ca. 31% yield). Diol 5 was also prepared after LiAlH4 reduction of the major aldol formed in the condensation between the lithium enolate of 2,6-di-tert-butyl-4-methylphenyl propanoate and (*)-2-methylvaleraldehyde (ca. 50 % overallyield). Intramolecular alkylation (t-BuOK,THF) of 6 or 7 gave a 4060 mixture of (&)-1and its C(3) epimer. Catalytic hydrogenation of unsaturated lactone 17 afforded W-1 in 80% yield. approach could benefit from the intramolecularalkylation in the construction of the 6-lactone ringg (Scheme I).
The red imported fiie ant (Solenopsisinuicta) is anative species of South America, and since ita introduction from Brazil in 1940, it has attained pest status in the southeastern United States.' It is best known for its aggressive behavior and painful sting and has resisted attempts of population control with chlorinated pesticides.2 In 1974, Jouvenaz et ala3reported on the queen pheromone of this species, and Glancey et aL4have shown that pentane extracts of the queens are highly attractive to workers and that the behavior patterns observed suggested that the pheromone might have potential for the development of specific control methods. The composition of the queen recognitionpheromonewas established by Rocca et al.? and the relative configuration of one of its components, namely tetrahydro-3,5-dimethyl-6-( ltmethylbutyl)-W-pyran-2-one(1,invictolide),was determined by total synthesis? The absolute configuration of ita natural form was established to be (3R,5R,6S,ltR)-1by Mori and Nakazono in 1986.' Since both the levorotatory and the racemic forms of invictolide (1) display pheromone activity, several syntheses have been described in the literature.68 Despite its conceivable origin in the polypropionate biosynthetic pathway, there has been no reported total synthesis of (+1 using stereoselective aldol condensationsto control the relative stereochemistry of the asymmetric centers present in 1. Furthermore it appeared to us that this
Results and Disaussion Our initial attempts to stereoselectively prepare aldol product 4a led us to explore the addition of the lithium enolate of the anti-selectiveBHT propionate (3)1° to (*I2-methylvaleraldehyde (Scheme 11). A 2 1 mixture of diastereoisomericaldols 4a and 4b was obtained in 96% yield after Kugelrohr purification. The Felkin isomer 4a was shown to be the major aldol after its isolation from LiChroprep Si60 (40-63-pm) column (64 % yield) and its conversionto the known (2RS,3SR,4RS)-2,4dimethyl-1,3heptanediol (5). The diol 5 was uneventfullyconverted to the 0-propionyl tosylate 6 and 0-propionyl iodide 7 which were employed in our studies on the internal alkylation as a direct route to the target 6-lactone ring. Our initial attempts with 6 and 7 using LDA as base, THF or THF/HMPA as solvent, and reaction temperatures ranging from -78 "C to room temperature met only with failure: either recovery of the starting material (1.5 equiv of LDA, THF, -78 to 25 "C) or its partial deprotection (LDA, THF/HMPA, -78 to 25 "C) was observed. Since we had evidence of formation of the lithium enolate under the conditions described above for a related system,12we turned our attention to the nature of the counterion as we reasoned that our failure might be due to a strong ionic pair being formed when LDA was employed. Although no improvementwas observedwhen
(1) LofPren. C. S.:Banks. W. A.: Glancey. B. M. Ann. Rev. Entomol.
isis;20, i.
(2) Summerlin,J. W.; Hung, A. C. F.; Vineon, S . B. Enuiron. Entomol. 1977,6, 193. (3) Jouvenaz, D. P.; Banks, W. A.; Lofgren, C. S . Ann. Entomol. SOC. Am. 1974,67,442. (4) Glancey, B. M.; van der Meer, R. K.; Lofgren, C. S.;Glover, A.; Tumlinson, J. H.; Rocca, J. R. Ann. Entomol. SOC.Am. 1980, 73, 609. (6) Rocca, J. R.;Tumlineon, J. H.; Glancey, B. M.; Lofgren, C. S. Tetrahedron Lett. 1983,24, 1889. (6) Rocca, J. R.;Tumlinaon, J. H.; Glancey, E. M.; Lofgren, C. S . Tetrahedron Lett. 1983,24,1893. (7) Mori, K.; Nakazono, Y. Tetrahedron 1986,42,6459. (8) For racemic totalsynthesisof (*)-1, see: (a)Reference 6. (b)Hoye, T. R.; Peck, D. R.; Tnunper, P. K. J. Am. Chem. SOC.1981,103,6618. (c) Hoye, T. R.; Peck, D. R.; Swaneon,T. A. J. Am. Chem. SOC.1984,106, 2738. (d) Schreiber, 5.L.; Wang, Z. J . Am. Chem. SOC.1986,107,6303. (e) Yamamoto, Y.; Taniguchi, K.; Maruyama, K. J. Chem. Soc., Chem. Commun. 1981, 1429. For total syntheses of ita natural form, see: (0 Ziegler, F. E.; Stirchak, E. P.; Wester, R. T. Tetrahedron Lett. 1986,27, 1229. (g) Reference 7. (h) Mori, K.;Senda, S . Agric. Biol. Chem. 1987, 51, 1379. (i) Wakamatau, T.; Nishikimi, Y.; Kikuiri, H.; Nakamura, H. Heterocycles 1987,26,1761. (j) Hoffman, R.W.; Ditrich, K.; Koeter, G.; Sturmer, R. Chem. Ber. 1989,122, 1783.
0022-32631931195&0338$O4.O0/ 0
(9) Nakai, E.; Kitahara, E.; Sayo, N.; Ueno, Y.; Nakai, T. Chem. Lett. 1985,1726. (10) Heathcock, C. H.; Pirrung, M. C.; Lampe, J.; Montgomery, S.H. Tetrahedron 1981,37,4087. (11) Ziegler, F. E.; Cain,W. T.; Kneidey, A.; Stirchak, E. P.; Wester, R.T. J. Am. Chem. SOC.1988, 110,6442. (12) Similar results were observed when the toeylate i (R= CH3) wan employed
i
Y
Enolization (LDA/THF, -78 OC) of compound i (R = CH&Hs) and trapping with CH3SS0&H3(-78 'C to rt) afforded toeylate ii, in 55% yield. (6
1993 American Chemical Society
J. Org. Chem., Vol. 58, No.2, 1993 389
Total Synthesis of (*)-Invictolide
Scheme 1118
Scheme I
WBU 2 OSiMe2tB,
OH 0
b-d_
PhAO+StBu
a
10 OH
0 R
O
W
14: R = CH2Ph 5:R=H 0
Scheme 118
0
OH
17
el 3
%
RO+
ll:X=OH 12: X = OTS 13: X = I
4
0
OH
5
PhAO+X
OH
1
LBU
R' = CH,; R2 = H
4a: Ar =*;
=e; 'BU
'BU
4b:Ar
R' = H; R2 = CH:,
LBU
a (a) 9, CHzClz, Tic&, -78 O C (65% yield); (b) LiAlHd, THF, rt (97% yield); (c) TaCl, CHZCl2, Et3N, -15 "C (85% yield); (d) NaI, acetone, reflux (73% yield); (e) EhCuLi, EBO, -78 "C rt (55% yield); (0Li, NHdl), -78 OC (94% yield); (g) (CH3CH2C0)20,CH&lz, EtsN, DMAP (cat.),rt (95% yield); (h) t-BuOK, THF, 0 "C (78% yield); (i) LDA, THF, -78 "C, then PhSeBr, -78 OC 0 OC and 30%
-
-
HzOdHOAc (50% yield); 0') HP,EtOH, PdIC (80% yield).
Scheme IV.
c-e
5: X = OH; R = H 6: X = OTS; R = CH3CH2CO
7: X = I; R = CHSCH~CO
l:R=P-CH, 1': R = a-CH,
(a) (i) LDA, THF, -78 "C; (ii) (*)-2-methylvaleraldehyde; (b) chromatography (64% yield); (c) LAHI, THF, rt (78% yield); (d) (i) TsCl, CHPClZ, EtsN, -15 OC; (ii) (CH&HzCO)zO, CHZC12, EtsN, DMAP (cat.), rt (92% overall yield); (e) NaI, acetone, reflux (73% yieId); (0t-BuOK, THF, 0 OC ( 7 5 7 8 % yield). a
NaH/HMPA13 or NaHhfDS/C6H614was employed, the desired &lactones 1/1' were isolated in good yields (7578%) when t-BuOK (4 equiv) in THF was used. The 40: 60ratio of &lactones1:l' observed in the internal alkylation of 6 and 7 correlates well with the ratio reported by Nakai et al.9 in the synthesis of the Prelog-Djerassi lactone. With a short route to the desired skeleton secured we turned our attention to the control of the relative configurationof the four asymmetric centers present in 1. Among the methodologies available in the literature for the stereoselective construction of intermediate 6, we decided to employ the one developed by Gennari and coworkers16(Scheme111)which features the TiCLpromoted addition of the silyl ketene thioacetal 8 to (*)-3-(benzyloxy)-2-methylpropionaldehyde(9). The guidelines for our choice were the high yields reported for this transformation, the advantage of using a mixture of the E and 2thioacetals without any deleterious effect in the stereochemical outcome of the reaction and the possibility of accessto the natural form of invictolidefrom commercially available (23)-methyl 3-hydr6xy-2-methylpropionate. The addition of silyl ketene thioacetal 8 (E/Z ratio = 87:13),prepared in 66% yield from tert-butyl thiopropionate, to an equimolarmixture of (f)-9 and Tic&,in CH2(13)Takahashi,T.;Hdigurhi, S.;Kamga, K.; Tsuji,J. J.Am. Chem. SOC.1978,100,7424. (14)Stork,G.;Uyeo,S.;Wakamatsu,T.;Grieco,P.;Labovitz, J. J. Am. Chem. SOC.1971,93,4946. (15) Gennari,C.; Beretta, M.G.; Bemardi,A.; Moro,G.; Scolaatico,C.;
Todeschini, R. Tetrahedron 1986,42,909.
10
a b
I_
16
15
(a) LiAlHk THF, rt (97% yield); (b)acetone, C&, PPTS, reflux yield); (c) Hg(OAc)z, MeOH (d) Hz, Pd/C, EtOH, HCOPH;(e) acetone, C&, PPTS, reflux (42% yield, 3 steps). a
(97%
Cln at -78 OC, afforded thioester 10 (65% yield) diastereomericallyhomogeneous by 'H- and W-NMR analyses. Ita relative stereochemistrywas unambiguouslyassigned16 after ita conversion to the corresponding acetonides 16 and 16 (Scheme IV);vicinal coupling constants of 2.1 and 10.2 Hz between H-3 and H-4 in 15 and 16,respectively, were fully consistent with the relative configurationof the three contiguous chiral centers present in W l . Thioester 10 was uneventfully converted to the iodide 13 in 60% overall yield, which was chain elongated with an excessof lithium diethylcupratel' (13 14,M 9% yield9 followed by hydrogenolysisof the benzyl group (Li/NHa(1)) to afford ( * I 4 in 94% yield. Lactonization of the 0-propionyl toeylate 6,as depicted in Scheme 11,led to a 4060 ratio of (*)-invictolide (1) and ita C(3) epimer (1'). Access to the correct stereochemistry at C(3) of (&I-1 was
-.
(16) See aleo: Nagaoka, H.; Kuhi, Y.Tetrahedron 1981,37,3873for the aesianment of the relative stereochemistry of (*)-ll and its stare-
oisomers. (17) Ethvllithium was m e n d from ethvl bromide and lithium wire in ether at -30 "C under edni&tion (40kHz)&d t r d e d with unnuh to the reaction flark. T h e use of ethyhagneaium bromide catalyx.ed by Kochi's reagent (Li&uC&)did not yield the coupliq product 14. (18) Oxetane iii w u the major product (49% yield) when toeylata 12 wan employed while the deaired alcohol 14wu formed only in 21% yield. With iodide 18,oxetane iii was formed as a byproduct in 20% yield.
PhnO
a iii
Pilli and Murta
340 J. Org. Chem., Vol. 58, No.2, 1993 gained through the catalytic hydrogenation of t h e unsaturated &lactone 17, the major product isolated after a-selenylation, oxidation, and elimination of the mixture of epimeric &lactones 1/ 1' (Scheme 111). (*I-Invictolide (1) was obtained as the major epimer (6:lratio by GC), and it could be easily distinguished from its C(3) epimer both by 1H-and 13C-NMR(see the Experimental Section).
The same sense of diastereoselection was observed in the catalytic hydrogenation of the exo &lactone, but the diastereoisomeric ratio observed in this case was only moderate. Although a clear rationalizationfor these results is still lacking, they are in accordancewith those described by Danishefsky et al.19 in the reduction of the unsaturated lactone 19 (eq 1). 0
0
mL, 20 mmol). After 15 min the solution waa cooled to -78 OC, propanoatelo (3) (5.53 g, and 2,6-di-tert-butyl-4-methylphenyl 20.0mmol) was added dropwise during 15min. After stirring for 45 min, 2-methylvaleraldehyde(2.00 g, 20.0 mmol) was added in one portion. The mixture was then allowed to stirr for 5 min at -78 "C when it was quenched by the addition of 10mL of saturated aqueous NHIC1. After warming up to room temperature, the reaction mixture was diluted with 50 mL of ether, and the organic phase was washed with 1%aqueous HCl(3 X 20 mL) and 5% aqueous NaHC03 (3 X 20 mL). Normal workup gave a 7030 mixture of the Felkin aldol 4a and the anti-Felkin aldol 4b (7.23 g, 19.2 mmol), in 96% yield, after Kugelrohr purification (1.0 mmHg, 110-120 "C). The pure aldols were obtained after medium-pressure column chromatography in silica gel (40-30 pm) and 5% ether in hexanes as the eluent. anti-Felkin aldol 4b: lH NMR 6 0.93 (t,J = 6.6, 3 H), 1.03 (d, J = 6.9,3 H), 1.32 (s,9 H), 1.34 (s,9 H), 1.43-1.48 (m, 5 H), 1.58 (8, br, 2 HI, 1.77 (m, 1 H), 2.32 (8, 3 HI, 2.92 (qt, J = 7.5, 1H), 3.55 (d, J = 4.2,l H), 3.66 (m, 1H), 7.14 (s,2 H); l3C NMR 613.63,14.39,17.23,20.53,21.55,31.31,31.56,31.63,34.33,35.30, 35.41,43.83,77.59,127.51,127.72,135.29,142.32,142.55,146.42,
i
1
i
1
19
In summary, (*)-invictolide (1) has been synthesized in 8 steps from 2,6-di-tert-butyl-4-methylphenyl propionate (14% overall yield) and in 10 steps from 3-(benzyloxy)2-methylpropionaldehyde (6% overall yield). The diastereoisomeric excess in the latter case was greater than 70%.
Experimental Section General. Unless otherwise noted, materials were obtained from commercial suppliersand used without further purification. Ether and tetrahydrofuran (THF) were distilled from sodium/ benzophenone immediately prior to use. Diisopropylamine, triethylamine, pyridine, hexamethylphosphoric triamide (HMPA), and dichloromethanewere distilled from CaHz immediatelyprior to use. All reactions involving organometallic reagents were carried out under a N2 or an Ar atmosphere. The normal processing of organic extracts consisted of washing the extract with water and brine, drying over MgSOd, filtration, and concentrationwith a rotary evaporator. Column chromatography were carried out with silica gel, 70-230 mesh, arid TLC plates were prepared with silica gel, 35-70 mesh. GC analyses were performed in a HP 5890A chromatograph with a 30-m X 0.53fused silica capillary column (cross-linkedpolymm x 1.3." (ethylene glycol) or 5% diphenyl-95 % dimethylpolyailoxaneas stationary phase) and Nz as the carrier gas. The GC-MS analyses were performed with a HP 5988A GC/MS system equipped with a 25-m X 0.20-mm X 0.33-mm fused silica capillary column (stationary phases above) and H2 as the carrier gas. Infrared spectra (IR) were determined as films in KBr with a PerkinElmer 399B or Perkin-Elmer 1600 FT-IR spectrophotometer. Mass spectra were measured with a Varian MAT 311A (70 eV) spectrometer. All NMRspedra were measured in CDClssolution, unless otherwise noted. 'H-NMR spectra were determined at 300 MHz and W-NMR spectra at 75.2 MHz (Varian Gemini), unless otherwise noted. Chemical shifts are expressed in ppm downfield from internal tetramethylsilane; coupling constants are expressed in hertz. lH-NMR data are tabulated in order: multiplicity (8, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; qt, quintuplet; m,multiplet; br, broad signal), coupling constante in hertz, and number of protons. Elemental analyses were performed on a Perkin-Elmer 2400 CHN Analyser at Instituto de Qulmica, UNICAMP).
(2SR,3SR,4RS)-2',6'-Di-tert-butyl-4'-methylphenyl3-Hydroxy-2,4-dimethylheptanoate(4a). To a stirred solution of diisopropylamine(2.23 g, 22 mmol) in 20 mL of THF at 0 "C was added dropwise a solution of n-BuLi in hexanes (1.60 M, 12.5
177.68. Felkin aldol 4a: lH NMR 6 0.93 (d, J = 6.6,6 H), 1.31 (8, 9 H), 1.32 (8, 9 H), 1.41-1.44 (m, 7 H), 1.70 (m, 1H), 2.32 (s,3 H), 2.85 (qt, J = 7.5, 1 HI, 3.66 (d, J = 2.1, 1 H), 3.80 (dd, J = 8.7 and 3.0,l H), 7.14 ( 8 , 2 H); 13CNMR b 12.05,13.02,14.35,20.62, 21.55,31.57,31.62,34.04,35.30,35.42,36.69,44.29,74.86,127.50,
127.73,135.28,142.31,142.51,146.42,177.86; IR 3530,1735, and 1600 cm-l; MS mlz 249 (5), 220 (71), 204 (32), 111(15), 83 (22), 71 (32), 57 (100). Anal. Calcd for CuHaOs: C, 76.55; H, 10.71. Found: C, 76.84; H, 10.36. (!ZRSfSR,4RS)-2,4-Dimethy 1-1f-heptanediol(5). Asolution of aldol 4a (1.69g, 4,5 mmol) in 10mL of THF was added dropwise to a stirred suspension of LiAlHl(O.34 g, 9.0 mmol) in 10 mL of THF at 0 "C. The mixture was stirred at room temperature for 20 h when it was diluted with 10 mL of ether. The mixture was cooled to 0 "C and treated with water (0.34 mL), 15% aqueous NaOH (0.34 mL), and water (1.0 mL),successively. The organic phase was separated by filtration, and the inorganicresidue was washed with ether (3 X 10 mL). Normal workup gave 1.65 g of a colorless oil which was chromatographed on silica gel (1:lC H r C12-ether) to afford diol 511 (0.56 g, 3.5 mmol) in 78% yield as a colorless oil: lH NMR (CDCls/DzO) 6 0.81 (d, J = 6.9, 3 H), 0.87 (d, J = 6.9, 3 H), 0.91 (t,J = 6.9,3 H), 1.21-1.44 (m, 4 HI, 1.66 (m, 1H), 1.85 (m, 1H), 3.47 (dd, J = 8.9. and 2.7,l H), 3.63 (dd, J = 10.8 and 7.8,l H), 3.72 (dd, J = 10.8 and 3.9,l H); 13C NMR (CDClJDZO) 6 12.26,13.59,14.29,20.43,34.82,36.31,37.27, 68.52,80.04; MS m/z 101 (58), 89 (loo), 71 (75), 59 (48), 58 (47), 57 (17), 55 (29), 43 (93).
(2RS,3SR,4SR)-2,4-Dimethyl-3-O-propionyl-l-O-(ptoluenesulfonyl)-1,3-heptanediol(6). To astirred solution of diol 5 (0.48 g, 3.0 mmol) in 5.0 mL of CH2Clz at -15 "C was added p-toluenesulfonyl chloride (0.57 g, 3.0 mmol) and triethylamine (0.32 g, 3.2 mmol). The reaction mixture was kept at -15 "C for 3 h when it was diluted with 10 mL of CHzCl2 and washed with 1% aqueous HCl(2 X 5.0 mL), and after the normal workup the crude tosylate (0.90 g) was taken up in 6.0 mL of CHzC12 and treated with propionic anhydride (0.37 g, 2.85 mmol), triethylamine (0.28 g, 2.85 mmol), and a catalytic amount of 4-(dimethylamin0)pyridine(0.005 g, 0.04 mmol). The reaction mixture was allowed to atirr for 30 min at room temperature when it wa8 diluted with 20 mL of CH2Cl2 and washed with 1% aqueous HCl (2 X 10 mL). After normal workup and column chromatography (5% ether-hexanes), 6 (1.02 g, 2.76 mmol) was obtained in 92% yield IR 1736,1598,1362,and 1178 cm-1; 1H NMR 6 0.81 (d, J = 6.6,3 H), 0.84 (t, J = 6.9,3 H), 0.92 (d, J = 6.9, 3 H), 1.09 (t, J = 7.5, 3 H), 1.27 (m, 4 H), 1.67 (m, 1 HI, 2.12 (m, 1 HI, 2.25 (9, J = 7.5, 2 H), 2.45 (8, 3 H),3.76 (dd, J = 9.6 and 7.2, 1 H), 3.99 (dd, J = 9.6 and 4.2, 1H), 4.75 (dd, J = 8.1 and 4.2, 1H), 7.34 ( d , J = 8.4,2 H), 7.77 (d, J = 8.4,2 H); 13C NMR 6 9.30,13.34, 14.14,20.08,21.63,27.57,33.81,34.81,35.76,71.99,76.66,127.98,
129.77, 132.88,144.72, 173.96. Anal. Calcd for C1g€€900&: C, 61.60; H, 8.16. Found C, 61.75; H, 8.43.
(2SR,3SR,4RS)-l-Iodo-2,4-dimethyl-3-O-p~p~onyl-3-he~(19) Danishefsky, 5.;Kato, N.; hkin, D.; Kerwin, J. F. J . Am. Chem. SOC.1982,104, 360.
tanol(7). To a solution of sodium iodide (0.23 g, 1.54 mmol) in 1.0 mL of acetone was added tosylate 6 (0.28 g, 0.75 "01)
Total Synthesis of (+I-Invictolide dissolved in 1.0 mL of acetone. The mixture was refluxed for 3 h, cooled to room temperature, and worked up as usual. Column chromatography of the crude product (5% ether-hexanes) afforded iodide 7 (0.18 g, 0.55 mmol) in 73% yield: IR 1740, 1465,1190 cm-1; lH NMR (CC4,80 MHz) 6 0.80 (d, J = 7.0,3 H), 0.85 (t,J = 7.0,3 H), 1.00 (d, J = 6.0,3 H), 1.15 (t,J = 7.0, 3 H), 1.2-1.7 (m, 5 H), 1.8-2.0 (m, 1 H), 2.25 (q, J = 7.0, 2 H), 2.9 (dd, J = 7.0 and 10.0, 1H), 3.20 (dd, J = 4.0 and 10.0, 1 H), 4.7 (q, J = 6.0, 1 H). Anal. Calcd for C12Ha021 C, 44.18; H, 7.11. Found: C, 44.54; H, 7.35. (3RS,SRS,GSR,YRS)- and (3SR,5RS,6SR,l'Rs)-Tetrahydro6 4 l'-methylbutyl)-3,5-dimethyl-2iY-pyran-2-one (1 and 1'). To a stirred solution of t-BuOK (0.25 g, 2.24 mmol) dissolved in 4.5 mL of THF at 0 "C was added dropwise a solution of 6 (0.20 g, 0.55 mmol) dissolved in 1.0 mL of THF. After the mixture was stirred for 30 min, 1.0 mL of ethanol was added followed by the addition of saturated aqueous NHlCl(3.0 mL), and the mixture was allowed to stir for 30 min at room temperature. Normal workup gave 0.110 g of the crude product which was chromatographed on Florisil (5% ether-hexanes) to afford a mixture of &-lactones111' (0.085 g, 0.43 mmol), in 78% yield, as a 4060 mixture by capillary GC. (&)-Invictolide (1):Ej IR 1730 and 1185 cm-l; lH NMR 6 0.90 (d, J = 6.9, 3 H), 0.91 (d, J = 6.9, 3 H), 0.97 (d, J = 6.7, 3 H), 1.22 (d, J = 6.9, 3 H), 1.31-1.48 (m, 4 H), 1.68 (t,J = 8.1, 2 H), 1.72 (m, 1H), 1.72-2.04 (m, 1H), 2.74 (m, 1H), 3.91 (dd, J = 10.1 and 2.0,l H); 13CNMR 6 12.31,14.15,16.59,17.68,20.46,28.44, 32.58,33.67,35.46,36.14,85.85,176.50; MS mlz 198 (M, 31,156 (19), 127 (87), 99 (48), 69 (26), 56 (100). (&)-3-Epiinvictolide (1'): lH NMR 6 0.86 (d, J = 6.8,3 H), 0.88 (t, J = 6.9, 3 H), 0.94 (d, J = 6.4, 3 H),1.26 (d, J = 7.1, 3 H), 1.31-1.52 (m, 4 H), 1.63-1.74 (m, 2 H), 1.83-1.99 (m, 2 H), 2.46 (m, 1H), 3.93 (dd, J = 10.1 and 1.6,l H); 13CNMR 6 12.35, 14.12,17.23,17.33,20.45,30.97,34.06,35.95,36.33,37.79,89.36, 174.92. (2RS,3SR,4RS)-l-O-Benzy1-2,4-dimethyl-l,3,5-~entanetriol (11). To a stirred suspension of LiAlHd (0.14 g, 3.7 mmol) in 3.0 mL of THF at 0 OC was added dropwise a solution of thioester 10l6(0.60 g, 1.85 mmol) dissolved in 3.0 mL of THF. After 20 h at room temperature the reaction was quenched by the addition of water (0.15 mL), aqueous 15% NaOH (0.15 mL), and water (0.45 mL), successively. Extraction with ether (3 X 20 mL) followed by normal workup gave 1lls(0.43 g, 1.80 mmol) in 97 % yield IR 3410,1460,735,and 700 cm-'; lH NMR ( c a s ) 6 0.59 (d, J = 6.9,3 H), 0.97 (d, J = 6.9,3 H), 1.58 (m, 1H), 1.86 (m, 1H), 3.32 (m, 2 H), 3.58 (a, br, 2 H),3.69 (m, 3 H), 4.21 (s, 2 H), 7.16 (m, 5 H); 13C NMR ( C a s ) 6 9.13,13.43,36.60, 37.08, 67.71, 73.75, 76.29, 78.22, 128.16, 128.30, 128.36, 138.49. (2RS,3RS,4RS)-5-OBenzyl-2,4-dimethyl-l0-(ptolueneeulfonyl)-l,3,5-pentanetriol(12). The same procedure described for 6 afforded crude tosylate 12 in 85% yield 'H NMR 6 0.74 (d, J = 7.0,3 H), 0.84 (d, J = 6.9,3 H),1.92 (m, 1H), 2.00 (dq, J = 7.0 and 2.3,l H), 2.43 (a, 3 H), 2.96 (a, br, 1H), 3.45 (t, J = 8.9,l H), 3.55-3.61 (m, 2 H), 3.89 (dd, J = 9.4 and 6.7,l H), 4.09 (dd, J = 9.4 and 7.5,l H), 4.50 (8, 2 HI, 7.26-7.40 (m, 7 H), 7.79 (d, J = 8.4,2 H); 13C NMR 6 8.66,12.98,21.62,35.34,35.61, 73.37,73.58,75.12, 76.52, 127.69,127.93, 128.51, 129.77, 133.14, 137.41,144.58. Asample was purified by column chromatography (10% ether-hexanes) for elemental analysis. Anal. Calcd for CplHsOsS: C, 64.26; H, 7.19. Found: C, 64.41; H, 7.41. (2SR,3RS,4RS)-S-O-Benzyl-l-iodo-2,4-dimethyl-3,5-pentanediol(l3). The same procedure as described for 7 afforded iodide 13 in 73% yield 1H NMR 6 0.79 (d, J = 7.0, 3 H), 1.01 (d, J = 6.7,3 H), 1.88 (dq, J = 7.0 and 2.4, 1 H), 1.95 (m, 1 H), 3.19 (dd, J = 9.5 and 6.6, 1 H), 3.36 (dd, J = 9.5 and 7.7, 1 H), 3.50 (t, J = 9.0, 1 H), 3.61 (dd, J = 9.1 and 3.9, 1 H), 3.66 (dd, J = 8.0 and 2.4, 2 H),4.51 (d, J = 12.0, 1 H), 4.54 (d, J = 12.0, 1H), 7.32 (m, 5 H); l3C NMR 6 12.89,13.19,13.31,36.14,38.72, 73.58, 76.37, 77.97, 127.70, 127.88, 128.50, 137.39; MS mJz 172 (241, 155 (40), 107 (49), 91 (100). (2RS,3SR,4RS)-1-OBenzyl-2,4-dimet hyl- 1,3-heptanediol (14). To a stirred suspension of CuBr.Me2S (1.0 g, 5.0 mmol) in 3.5 mL of ether at -78 OC was added a 1.5 M solution of EtLi in etherl' (7.0mL, 10.5mmol). The reactiontemperature was raised to -30 "C when a brown color develops, and after 30 min the reaction was cooled back to -78 OC and a solution of 13 (0.35 g,
J. Org. Chem., Vol. 58, No.2, 1993 341 1.0 mmol) in 4.0 mL of ether was added dropwise. The reaction mixture was warmed up to room temperature, and after 30 min it was quenched with 10% NH4OH saturated with NHlCl(20 mL). Normal wmkup followed by PTLC (5% ethephexanes) afforded 14 (0.138 g, 0.55 mmol) as a colorless oil in 55% yield and oxetane iii (0.070 g, 0.32 mmol) as a colorless oil in 32% yield. 14: lH NMR 6 0.83 (d, J = 7.0, 3 H), 0.86 (d, J = 6.7, 3 H), 0.87 (t,J = 7.0, 3 H), 1.22-1.43 (m, 5 H), 1.98 (m, 1 H), 3.38 (a, br, 1 H), 3.41 (dd, J = 8.4 and 2.8, 1H),3.50 (t, J = 8.6, 1 H), 3.60 (dd, J = 8.6 and 4.2,l H), 4.52 (8, 2 H), 7.32 (m, 5 H); 13C NMR6 12.39,13.72,14.34,20.50,34.86,35.98,36.45,73.56,76.32, 79.03, 127.71, 127.77, 128.45, 137.73; MS mlt 120 (31, 108 (31), 91 (1001, 87 (25). Anal. Calcd for C1SHp~02:C, 76.75; H, 10.47. Found C, 76.89; H, 10.13. Oxetane iii: lH NMR 6 0.86 (d, J = 6.7,3 HI, 1.24 (d, J =
7.1,3H),2.31(m,lH),2.95(m,lH),3.30(dd,J=9.0and7.1, 1H), 3.55 (dd, J = 9.0 and 3.3,l H),3.95 (t,J = 10.3,l H), 4.50 (a, 2 H), 4.60 (dd, J = 10.7 and 7.3, 1 H), 4.76 (dd, J = 7.2 and 5.8,1H),7.32(~,5H);~3CNMR612.54,13.68,31.&1,35.20,71.27, 73.24, 75.04, 85.41, 127.37, 127.54, 128.27, 138.75; MS mlz 113 (3), 107 (31), 91 (loo), 71 (29). (2RS,3SR,4RS)-2,4-Dimet hy 1-1,3-heptanediol (5). To a stirred solution of lithium (0.060g, 10 mmol) in 50 mL of liquid ammonia at -78 "C was added alcohol 14 (0.087 g, 0.35 mmol) dissolved in 2.0 mL of THF. After 2 h a t -78 OC the reaction was quenched with solid NHlCl(2.0 g), and it was let to warm up to room temperature. Normal workup and column chromatography (1:l CH2C12-hexanes) afforded diol 5 (0.053 g, 0.33 mmol) as a colorless oil in 94% yield. (2RS,3RS,4RS)-5-0-Benzyl-2,4-dimethyl-1,30-isopropylidene-1,3,5-pentanetriol(l5). To a stirred solution of diol 11 (0.10 g, 0.42 mmol) in 20 mL of benzene were added acetate (0.5mL) and a catalytic amount of pyridiniump-toluenesulfonate (0.01 g, 0.04 mmol). The reaction was refluxed with removal of water (Dean-Stark) for 2 h. Normal workup afforded acetonide 15 (0.11 g, 0.41 mmol) as a colorless oil in 97% yield lH NMR 6 0.94 (d, J = 6.9,3 H), 1.06 (d, J = 6.9,3 H), 1.37 (a, 3 H), 1.39 (a, 3 H), 1.53 (m, 1H), 1.80 (m, 1H), 3.45 (dd, J = 14.7 and 6.1, 1H), 3.49 (dd, J = 14.7 and 3.0,l HI, 3.59 (dd, J = 13.2 and 1.5, 1H), 3.76 (dd, J = 13.2 and 2.1,l H), 4.09 (dd, J = 5.7 and 2.7, 1H), 4.45 (d, J = 12.0, 1H), 4.51 (d, J = 12.0, 1 H), 7.33 (8, 5 H); 13CNMR610.24,12.65,19.11,29.69,29.87,35.57,67.47,72.24, 72.40, 73.42, 98.92, 127.80, 127.94, 128.71, 139.44; MS mlz 278 (M, 3), 263 (35), 220 (20), 148 (33), 107 (831, 91 (100). (2SR,3RS,4RS)-Methyl5-OBenzyl-2,4-dimet hyl-3,S-dihydrosypentanoate. To a stirred solution of mercuric acetate (0.20 g, 0.62 mmol) in 2.0 mL of methanol was added aldol 10 (0.10 g, 0.31 mmol), and the reaction mixture was kept at room temperature for 1h. The reactionmixture was diluted with ligroin (20 mL), the inorganic solids were filtered off, and the organic phase was worked up as usual to afford the crude product (0.070 g) which was used without further purification: lH NMR 6 0.92 (d, J = 7.2, 3 H),1.19 (d, J = 7.2, 3 HI, 1.89 (m, 1H), 2.62 (dq, J = 7.2 and 4.2, 1 H), 3.55 (dd, J = 9.0 and 6.6, 1 H), 3.59 (d, J = 3.5,l H), 3.63 (dd, J = 4.5 and 9.0,l H), 3.69 (a, 3 H), 3.90 (m, 1 H), 4.51 (a, 2 H), 7.32 (a, 5 H); 13C NMR 6 9.80, 13.93, 35.89, 42.54, 51.87, 73.70, 74.80, 76.02, 128.04, 128.13, 128.82, 138.21, 176.64; MS mlz 266 (M, 2), 235 (81,179 (231, 160 (16), 142 (61), 108 (58), 107 (46), 92 (421, 91 (loo), 57 (46). (2SR,3RS,4RS)-Methyl3,5Oisopropylidene-2,4-dimethyl3,s-hydrosypentanoate (16). To a solution of the foregoing ester (0.067 g, 0.25 mmol) in 5 mL of ethanol containing 0.5 mL of formic acid was added 10% Pd/C (0.03 g), and the mixture was shaken under 4 atm of H2 (Parr apparatus) for 5 h. The catalyst was removed by filtration on Celite, the organic phase was neutralized with saturated NaHC03, and after normal workup the colorless oil (0.45 g) was dissolved in benzene (4 mL), acetone (0.10 mL) and pyridinium p-toluenesulfonate (0.001 g) were added, and the solution was refluxed with removal of water (DeanStark) for 2 h. The reaction was cooled to room temperature, and after normal workup the residue was chromatographed (5% ether-hexanes) to afford 16 (0.028 g, 0.13 mmol) in 52% yield as a colorless oil: 1H NMR 6 0.75 (d, J = 6.9,3 H), 1.16 (d, J = 7.2, 3 H), 1.34 (a, 3 H), 1.40 (a, 3 H), 1.82 (m, 1HI, 2.65 (dq, J = 7.2 and 3.6, 1 H), 3.52 (t,J = 10.8, 1 H),3.64 (a, 3 H), 3.65 (m, 1H),
342 J. Org. Chem., Vol. 58, No.2, 1993
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Pilli and Murta
4.02 (dd, J 10.2 and 3.6,1 H); '3c NMR 6 9.08,12.23,18.96, 1.6,3H), 2.63 (m, 1 H), 3.97 (dd, J = 11.1 and 2.4,lHI, 6.33 (d, J = 1.6,lH); W NMR 6 13.18,14.12,16.22,16.86,20.39,31.06, 31.18,41.10,51.69,66.07,75.32,98.37,174.90. 33.49,35.64,86-10,127.14,146.39, 166.29;IR 1702,1640, and (SSR,GSR,l'RS)-S,6-Dihydro-6-( 1'-met hylbutyl)-3,S-di1150cm-I. Anal. Calcd for C12H2002: C, 73.43;H, 10.27. Found methyl-2H-pyran-2-one(17). To a stirred solution of diisoC, 73.75;H, 10.42. in 1.0 mL of THF at 0 OC was propylamine (0.111g, 1.1 "01) 18: 'H NMR 6 0.90 (t, J = 6.9,3HI, 0.91 (t, J = 6.9,3H), 0.97 After 15 min the added 1.5 M n-BuLi (0.67 mL, 1.0 "01). (t, J = 7.2,3H),1.28-1.57 (m, 4 H), 1.70 (m, 1 H), 1.95 (m, 1 H), solution was cooled to -78 OC, and 1/1' (0.098 g, 0.5 mmol) 2.28 (m, 1 H), 2.66 (dd, J = 15.9 and 4.5,l HI, 3.96 (dd, J 9.6 dissolved in 0.5 mL of THF was added dropwise. After 30 min and 2.1,1 HI, 5.52 (d, J = 1.2,1 H), 6.39 (d, J = 1.2,1 H). a solution of phenylselenenyl bromide (0.235g, 1.0 "01) in 1.0 (3RS,SRS,GSR,l'RS)-Tetrahydro-6-(1'-methylbuty1)-1,smL of THF was added, and the reaction mixture was stirred at dimethyl-W-pyran-2one (1). To asolution of lactone 17 (0.025 -78 OC for 2 h and then warmed up to 0 OC when a sohtion of g, 0.125 mmol) in 8 mL of ethanol was added a catalytic amount 30% H202 (0.70mL) and acetic acid (0.15mL) in water (1.0mL) of 1096 Pd/C (2mg),and the mixture was shaken (Pmapparatus) was added. The reaction mixture was allowed to warm up to under 4 atm of hydrogen for 17 h. The catalyst was removed by room temperature, and after stirring for 30 min it was poured filtration on Celite, the solvent was removed under reduced into a mixture of saturated NaHCOs (20mL) and 1:l etherpressure, and the residue was chromatographed on Florisil (10% hexanes (20mL). The organic phase was washed with water (2 ether-hexanes) to afford (f)-1(0.020g, 0.10 mmol, 80% yield). X 10 mL), 1 % HCl(2 X 10mL), and brine (10mL). The organic The 'H- and 1%-NMR spectra were fully consistent with those phase was dried over MgSO, and evaporated to afford 0.085g of reported by Hoffman et al.ej a pale yellow oil which was purified by PTLC (10% etherhexanes): 17 (0.048g, 0.25 mmol, 50% yield) and 18 (0.025 g, Acknowledgment. Financial support from FAPESP, 0.13 mmol, 26% yield). 1 7 1HNMR60.90(t,J=7.0,3H),0.95(d,J=6.9,3H),1.05CNPq, and International Foundation for Science are gratefully acknowledged. (d, J = 7.2,3H), 1.26-1.51 (m, 4 H), 1.73 (m, 1 H), 1.90 (d, J =
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